基于酵母微囊构建仿生型口服肿瘤靶向递送系统及其靶向机制研究

Targeting delivery drug by oral administration is a focused but difficult problem in oral drug delivery area. The research of novel oral drug delivery systems has made extensive progress on local targeting of gastrointestinal tract. However, orally targeted delivering drug to parenteral tissues is still facing great challenges. On the other way, the bionic delivery system provide a new research idea to achieve orally tumor targeted drug delivery on the lesions outside gastrointestinal tract in the past years, but the lacks of drug loading diversity, flexibility and efficiency are severely limiting its development. In the previous experiments, we found that yeast microcapsules can successfully load nanoparticle by electrostatic attraction, and this microcapsule was found to be orally targeted delivered to tumor in nude mice with transplanted tumor, indicated that yeast microcapsules could be used to construct oral tumor targeted drug delivery system by bionic simulating the gastrointestinal microbial infection route of yeast and other fungus. Therefore, this project intends to select trabectedin as a model drug to prepare drug loaded yeast microcapsules, chose mice fibrosarcoma MN/MCA1 as tumor model to construct oral tumor targeted drug delivery system and preliminarily investigate its targeting mechanism by in vivo imaging, fluorescent tracer, etc. The successful construction of the system is expected to provide an effective oral tumor targeting strategy for clinical chemotherapy drugs and new insight to design novel oral targeted delivery system.

口服靶向是口服释药系统研究的焦点与难点。尽管其在胃肠道局部靶向方面已取得了诸多进展，胃肠道外远隔组织的靶向研发仍面临巨大挑战。另一方面，仿生药物递送系统为实现口服靶向系统的设计提供了新的思路，但其在负载药物的多样性、灵活性和负载率等方面存在的问题严重限制了其发展，且其在口服肿瘤靶向治疗中的有效性仍需深入研究。申请人前期发现基于静电作用可将纳米粒高效富集于酵母微囊中，并在裸鼠移植瘤模型中发现该酵母微囊口服后可靶向至肿瘤部位，提示载药酵母微囊可通过模拟微生物胃肠道感染途径实现口服肿瘤靶向。为此，本项目拟以曲贝替定为模型药物制备载药酵母微囊，建立小鼠纤维肉瘤MN/MCA1模型，通过活体成像、荧光示踪等方式对酵母微囊的口服肿瘤靶向特性及机制进行探讨，并深入研究其靶向治疗效果。该项目的成功实施有望为肿瘤的口服靶向治疗提供极具临床应用前景的潜在新制剂，并为新一代口服靶向递送系统的构建提供新的设计理念。

口服靶向给药一直是药物递送领域中的难点问题。本项目成功构建了一种酵母衍生的顺铂靶向口服给药平台。首次确定了制备酵母微胶囊（YCs）的最佳工艺条件。通过将顺铂制备为顺铂前体纳米颗粒后，将其成功负载于酵母微囊中，成功获得了可经口服给药后靶向递送至肿瘤病灶的顺铂酵母微囊，该顺铂酵母微囊可以在模拟胃肠道条件的缓冲液中释放顺铂。体外实验表明，酵母微囊可被巨噬细胞迅速内吞，并并能长时间滞留于巨噬细胞中。顺铂酵母微囊对不同肿瘤细胞（包括耐药细胞）具有较强的细胞毒作用，提示载于酵母微囊中的顺铂前体纳米粒在细胞内释放后仍保持活性。口服给药后，酵母微囊通过巨噬细胞介导的淋巴系统移位实现了在A549小鼠人肺癌异种移植瘤中的药物口服靶向递送。通过这种靶向作用，口服顺铂酵母微囊对A549荷瘤小鼠显示出良好的疗效，与静脉注射游离顺铂相当。然而，口服游离顺铂不能产生抗肿瘤作用。此外，口服顺铂酵母微囊比口服或静脉注射游离顺铂更安全。因此，这种仿生方法可以作为一种有效的策略，开发基于顺铂或其衍生物的靶向口服化疗药物。另外，基于酵母微囊载药量低的问题，在完成项目主要工作的同时，申请者持续通过多重非共价键自组装与无载体自组装研究提高酵母内负载的纳米粒载药量问题，也取得了重要的突破，获得了载药量为100%的无载体纳米药物。